The NF1-encoded protein, neurofibromin, has been known to biochemically function as a Ras-GTPase activating protein (RasGAP) for over fifteen years. However, despite this knowledge little is known about the critical downstream effector pathways involved in disease pathogenesis. We have recently demonstrated that mTOR, a kinase implicated in the development of a variety of familial cancer syndromes, is critically deregulated in response to NF1 mutations. Moreover, we have shown that NF1-deficient tumor cells are highly sensitive to mTOR inhibitors, and newer preliminary studies suggest that these inhibitors are effective in inhibiting the growth of tumors in mice. The central goal of this proposal is to elucidate the importance of the mTOR pathway in NF1-associated tumorigenesis. Our preliminary data in primary Nf1-deficient mouse cells, human tumor cell lines, and a genetically engineered mouse model, suggest that this pathway critically contributes to the tumorigenic process. Therefore one of the Aims of this proposal is designed to determine whether rapamycin, an mTOR inhibitor, represents a viable therapy for NF1, using various mouse models. However, while mTOR inhibitors are likely to be therapeutically useful agents, we also aim to define additional components of this pathway. In particular, we intend to identify other kinases that function upstream or downstream of mTOR, as they are potential targets for small molecule inhibitors. These studies will not only contribute to our understanding of NF1 pathogenesis but will also impact the development of future therapies. Specifically, if we are able to demonstrate that rapamycin is an effective agent in mouse models of MPNST, these data should stimulate future clinical trials. Moreover, by mechanistically dissecting the mTOR pathway in this context we are likely to identify additional therapeutic candidates. This information should provide insight into the pathogenesis of NF1 as well as other cancers in which the Ras pathway is deregulated. [unreadable] [unreadable] [unreadable]